Direct and indirect antioxidant properties of inducers of cytoprotective proteins

Cellular protection against oxidative and electrophile toxicities is provided by two types of small-molecule antioxidants: (i) direct antioxidants, which are redox active, short-lived, are sacrificed in the process of their antioxidant actions and need to be replenished or regenerated, and may evoke pro-oxidant effects; and (ii) indirect antioxidants, that may or may not be redox active. Indirect antioxidants activate the Keap1/Nrf2/ARE pathway resulting in transcriptional induction of a battery of cytoprotective proteins (also known as phase 2 enzymes) that act catalytically, are not consumed, have long half-lives, and are unlikely to evoke pro-oxidant effects. These protective systems are involved in a complex functional interplay, such that many cytoprotective proteins participate in the synthesis and/or regeneration of direct antioxidants, whereas some direct antioxidants are required for the catalytic functions of cytoprotective proteins. Importantly, many inducers of cytoprotective proteins have been isolated from edible plants, e.g., sulforaphane from broccoli and curcumin from turmeric. Both are pleiotropic agents with multiple biological activities that could collectively contribute to their protective effects in various animal studies, including models of carcinogenesis, hypertension, neuronal and retinal damage. In addition to inducing cytoprotective proteins, molecules like curcumin which contain Michael acceptor functionalities (olefins or acetylenes conjugated to electron withdrawing groups) and phenolic hydroxyl groups can scavenge directly and potently oxygen- and nitrogen-centered reactive intermediates. Such bifunctional antioxidants can play a dual protective role by: (i) scavenging hazardous oxidants directly and instantaneously, and (ii) inducing cytoprotective enzymes that in turn function to resolve the consequences of hazardous processes that are already in progress, and to ensure long-term protection against subsequent challenges.